Proliferative vitreoretinopathy (PVR) is the most common cause of ultimate failure of retinal reattachment surgery. Specific prophylaxis and treatment are lacking largely because the pathogenesis of PVR is poorly understood. There is good evidence to suggest that cell de- differentiation migration, and proliferation are important processes, however, the nature and origin of the stimuli for these processes are unknown. This proposal is aimed at identifying the stimuli for these processes and the manner by which they gain access to the vitreous cavity. Studies will be performed in human RPE and retinal glia in vitro and in rabbit models of PVR in vivo. Cellular differentiation will be assessed by ultrastructural criteria and intermediate filament expression detected by immunohistochemistry. Cellular migration will be assessed by Boyden chamber assays in vitro and by sequential morphologic analysis in vivo. Cellular proliferation will be assessed by [3H] thymidine incorporation, growth curves, and ornithine decarboxylase activity in vitro and by [3H] thymidine incorporation in vivo. Agents that will be examined include those that have been demonstrated to affect cellular differentiation, including phorbol esters, retinoids, and cyclic AMP as well as several different growth factors. Several agents will also be examined for their ability to inhibit the above cellular processes as well as the development of traction retinal detachment formation in animal models. Investigations concerning access of stimulatory agents to the vitreous will focus on the blood-retinal barrier, cell-derived agents (inflammatory and non-inflammatory) and retina-derived agents. The role of the blood-retinal barrier breakdown will be examined by vitreous flourophotometry and tracer studies. Other studies will investigate pharmacologic and cell-mediated modulation of the barrier. The contribution of cell-derived agents will focus on modulation of platelet- derived growth factor-like proteins produced by RPE in culture and the role of inflammation in animal models of PVR. The potential role of retina-derived agents will be examined by immunoblots of subretinal fluid obtained from retinal detachment patients. In this manner, we hop to gain a more detailed picture of the pathogenic mechanisms involved in PVR so that strategies to prevent and interrupt them can be designed.